The bacterium Bartonella henselae causes a variety of disease syndromes including severe systemic infections in some patients, particularly in immunocompromised individuals. One manifestation of this emerging infectious agent is bacillary angiomatosis which is characterized by the presence of vascular proliferative lesions of the skin and visceral organs in infected patients. The goal of this project is to test the central hypothesis that B. henselae utilizes coordinate regulation of several virulence factor genes to enhance it's ability to promote angiogenesis. At least two important virulence factors have been identified in B. henselae that play a role in causing angiogenesis. The first is the virB operon that encodes a type IV secretion system that is responsible for delivery of the effector proteins that act on endothelial cells to promote their extended survival. The second is the major adhesin BadA that is on the surface of B. henselae and has been shown to be important in inducing vascular endothelial growth factor secretion in infected cells. Our preliminary data suggest that the two-component regulatory system OmpR/EnvZ of B. henselae is at least in part responsible for regulation of these genes. The following specific aims are proposed to test the hypothesis;1) define the correlation between ompR and envZ expression and expression of the virB operon, 2) characterize the mechanism involved in ompR/envZ upregulation of virB, and 3) identify other virulence factor genes under control of ompR/envZ . These studies should help us understand how and why this bacterium causes mild disease in some patients and life-threatening infections in other patients resulting in angiogenic lesions. Furthermore, characterization of a gene regulatory system that controls bacterial virulence factors may prove to be a valuable target for antimicrobial therapy. An applied product of this project is the description of the regulatory mechanism of the virB type IV secretion system genes. Such information may prove valuable in future attempts to harness the use of this secretion system for delivery of DNA and protein to target cells for gene therapy. Narrative Project Description The bacterium Bartonella henselae causes a variety of disease syndromes including severe life-threatening infections in some patients, particularly in immunocompromised individuals. The unique aspect of this severe disease is the proliferation of blood vessels, or angiogenesis. This project seeks to better understand how the genes of this bacterium are controlled to cause this angiogenesis. Characterization of a gene regulatory system that controls bacterial virulence factors may prove to be a valuable target for antimicrobial therapy to prevent infections caused by B. henselae.